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Subclone Eradication Analysis Identifies Targets for Enhanced Cancer Therapy and Reveals L1 Retrotransposition as a
Kirsi Ketola1, Heidi Kaljunen2, Sinja Taavitsainen3
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. kirsi.ketola@uef.fi steve.bova@tuni.fi.
Abstract:
Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance. SIGNIFICANCE: Differential analysis of eradicated and resistant subclones following cancer treatment identifies that L1 activity associated with resistance is induced by current therapies and blocked by the antiretroviral drug azidothymidine.
Insights
Differential Subclone Eradication and Resistance (DSER) analysis reveals that current cancer therapies can activate L1 transposons, contributing to resistance. Blocking L1 activity with drugs like azidothymidine may overcome this resistance.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Cancer treatment can eradicate sensitive subclones, but resistant subclones often persist, leading to relapse.
- Understanding the genomic differences between eradicated and resistant subclones is crucial for developing more effective therapies.
- Previous studies have shown treatment-induced genomic alterations in cancer, but direct comparison of eradicated vs. resistant subclones is less explored.
Purpose of the Study:
- To introduce Differential Subclone Eradication and Resistance (DSER) analysis for identifying therapeutic targets.
- To investigate the role of L1 transposon activation in treatment resistance in prostate cancer.
- To identify molecular targets that can convert resistant subclones into eradicable ones.
Main Methods:
- Developed and applied Differential Subclone Eradication and Resistance (DSER) analysis to pre- and post-treatment samples from a patient with BRCA2-deficient metastatic prostate cancer.
- Performed genomic analysis to compare eradicated and resistant subclones.
- Utilized RNA interference (RNAi) to deplete FANCI and assessed L1 transposon activation in various prostate cancer cell lines and xenograft models following different treatments.
Main Results:
- Identified FANCI and EYA4 as candidate DNA repair-related targets for enhancing subclone eradicability.
- Demonstrated that EYA4 alteration was linked to L1 transposon insertion during treatment evolution.
- Showed that carboplatin and enzalutamide induced L1 transposon activation in specific prostate cancer cell lines (LNCaP, VCaP) and in vivo models, which was inhibited by azidothymidine.
Conclusions:
- DSER analysis is a valuable tool for precision cancer medicine, particularly in cases of temporary metastatic regression.
- L1 transposon activation, induced by current therapies, represents a modifiable source of cancer genomic heterogeneity and a potential therapeutic target.
- Targeting L1 activity with agents like azidothymidine may offer a strategy to overcome therapy resistance.
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